Mode-actions of the Na+-Ca2+ exchanger: from genes to mechanisms to a new strategy in brain disorders

Mode-actions of the Na+-Ca2+ exchanger from genes to mechanisms to a new strategy for brain disorders were comparatively studied in oxidative stress. In transfected Chinese hamster ovary (CHO) cells steadily expressing the Na+-Ca2+ exchangerʹs gene, Ca2+-efflux via an active mode of the Na+-Ca2+ exchanger was elicited by hydrogen peroxide (H2O2) after preincubation of the cell with a Ca2+-free medium, whereas Ca2+-influx via a reverse mode of the Na+-Ca2+ exchanger was dramatically evoked by H2O2 after preincubalion of the cell with a Ca2+ medium, as a prelude to neuronal death. According to [45Ca2+] uptake of transfected CHO cells at given lime intervals or extracellular Na+[Na+]0 gradients, hyperbola, logarithmic and sigmoid curve equations of the Na+-Ca2+` exchangerʹs mode-actions were respectively defined in the absence and the presence of H2O2. The Na+-Ca2+ exchangerʹs conformational transition in oxidative stress was dominated by adenosine triphosphate (ATP)-dependent cytoskeletal redox modification, cation-π interactions and secondary Ca2+ activation. These mechanisms were used to generate an intracellularly distributed tetra-clusler (named VISA931) for rescuing G-protein agonist-sensitive signal transduction and cortico-cerebral somatosensory evoke potential (SEP) from oxidation via activating forward operation of the Na+-Ca2+ exchanger, the β-adrenergic and the P2-purinergic receptors, blocking Ca2+ influx and catalyzing the disrnutalion of Superoxide anions (O2 ) to H2O2. In conclusion, knowledge-based drug design is a new strategy for developing promising candidates of neuroproteclive agents.